We have continued our efforts to develop in vivo and in vitro models to better understand the mechanistic role of genes highly differentially expressed in lung cancers. We have generated transgenic mice carrying a gene, PGP9.5, which is often over expressed in lung cancers. We are collaborating with Dr. Ilona Linnoila's laboratory to examine these transgenic animals for transgene expression as well as potential tumor formation, life span changes, and to breed them with other lung cancer animal models. We have identified two founder animals that carry lung specific expression of the PGP9.5 gene. These animals are now being bred for Dr. Linnoila's laboratory as an collaboration to address the role of PGP9.5 over expression in lung epithelium to EMU induced lung carcinogenesis. Our second line of study involving functional analysis of SMAD6 protein that often shows reduced expression in lung cancers. Using immunohistochemical analysis we showed that SMAD6 expression in lung tumors is associated with an increased rate of tumor recurrence in adenocarcinomas. We propose that this is due to reduction if negative growth signaling by TGF-beta/BMP upon SMAD6 expression. We are using siRNA approach to determine if SMAD6 inactivation would lead to reduction in cell growth. We are also using modeling systems to determine if the presence of SMAD6 contribute to tumor genesis.